Control of Klebsiella capsule biosynthesis and attachment

克雷伯菌荚膜生物合成和附着的控制

• 批准号: 10713888
• 负责人: Laura Anzaldi Mike
• 金额: $ 38.63万
• 依托单位: UNIVERSITY OF TOLEDO HEALTH SCI CAMPUS
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2028-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10713888
• 关键词: Adherence; Amoeba genus; Anabolism; Area; Bacteria; Bacteriophages; Cell surface; Cells; Complex; Dehydration; Endogenous Factors; Environment; Environmental Protection; Epithelial Cells; Escherichia coli; Exogenous Factors; Foundations; Gastrointestinal tract structure; Genes; Genetic; Goals; Gram-Negative Bacteria; Heterogeneity; Human; Immune Evasion; Intervention; Klebsiella; Laboratories; Membrane; Metabolic; Metabolism; Microbial Biofilms; Modeling; Nutrient; Polysaccharides; Population; Predatory Behavior; Predisposition; Process; Production; Research; Sewage; Shapes; Signal Transduction; Soil; Source; Surface; Vision; bacterial fitness; capsule; environmental change; environmental stressor; extracellular; fitness; flexibility; gut bacteria; gut colonization; pressure; programs; response; ultraviolet irradiation

SUMMARY Capsular polysaccharide (CPS) is the outermost barrier between bacteria and their environment. It shapes bacterial interactions with external factors, including adherence to surfaces (e.g. biofilm formation, epithelial cell association); protection from environmental stressors (e.g., dehydration, UV irradiation); susceptibility to predation (e.g., phage, bacteria, or amoeba); or immune evasion (e.g. opsonophagocytosis). The Klebsiella species complex is comprised of non-fastidious Gram-negative bacteria that colonize diverse environments, including soil, sewage, sink drains, and mammalian guts. Klebsiella are early colonizers of the human gastrointestinal tract and, when environmental conditions shift in the gut, they have the potential to bloom and out-compete all other colonizers, including closely related Enterobacterales such as E. coli. Clearly, Klebsiella metabolic capacity is robust and flexible. Moreover, Klebsiella CPS production is required for efficient gut colonization and persistence. There is a major gap in our understanding of how exogenous signals are transduced through Klebsiella metabolism and intracellular regulatory networks to control CPS production and how that CPS is attached to the outer envelope. Our long-term goal is to understand how bacterial control of CPS biosynthesis and attachment shapes fitness in response to changing environmental pressures at both single cell and population levels. The objective of this application is to establish a model of the exogenous and endogenous factors that control Klebsiella CPS biosynthesis and cell surface attachment. We seek to establish a framework for understanding how Klebsiella and other Gram- negative bacteria integrate exogenous nutrient signals with their metabolic and regulatory networks to hone their fitness under varying environmental pressures. Recent progress in the laboratory has identified specific genes and some environmental signals that alter CPS attachment and abundance. Our proposed project areas are to examine (1) the mechanisms controlling CPS attachment and release at the outer membrane and (2) how external nutrient sources and cellular metabolism regulate CPS biosynthesis. The overall vision of our research program is to develop a model of how extracellular signals combined with genetic and regulatory heterogeneity create dynamic surface exposed glycans within a bacterial population to enhance overall fitness in the face of environmental challenges. This will provide the foundation for identifying potential intervention points that could be targeted to modulate bacterial CPS production and decolonize specific niches.

总结 荚膜多糖（CPS）是细菌与环境之间最外层的屏障。它 塑造细菌与外部因素的相互作用，包括粘附到表面（例如生物膜 形成，上皮细胞结合）;保护免受环境应激（例如，脱水，UV 照射）;对捕食的敏感性（例如，噬菌体、细菌或变形虫）;或免疫逃避（例如， 调理吞噬作用）。克雷伯氏菌属物种复合体由非苛养革兰氏阴性杆菌组成。 在不同环境中定居的细菌，包括土壤、污水、下水道和哺乳动物的肠道。 克雷伯氏菌是人类胃肠道的早期定居者，当环境条件 在肠道的转变，他们有可能开花和竞争超过所有其他殖民者，包括密切 相关的肠球菌目，如E.杆菌显然，克雷伯氏菌的代谢能力是稳健和灵活的。 此外，克雷伯氏菌CPS生产是有效的肠道定殖和持久性所必需的。有 我们对外源性信号如何通过克雷伯氏菌转导的理解存在一个主要空白 代谢和细胞内调控网络来控制CPS的产生，以及CPS是如何 附在外壳上。我们的长期目标是了解CPS的细菌控制 生物合成和附着塑造适应性，以应对不断变化的环境压力， 单细胞和群体水平。本申请的目的是建立一个模型， 控制克雷伯氏菌CPS生物合成和细胞表面的外源和内源因子 附件.我们寻求建立一个框架，了解克雷伯氏菌和其他革兰氏- 阴性细菌将外源营养信号与它们的代谢和调节网络整合， 在不同的环境压力下磨练它们的适应能力。实验室的最新进展 确定了改变CPS附着和丰度的特定基因和一些环境信号。 我们建议的项目范围包括研究（1）控制CPS附着的机制， 外膜释放和（2）外部营养源和细胞代谢如何调节 CPS生物合成。我们研究计划的总体愿景是开发一个模型， 信号与遗传和调节异质性结合产生动态表面暴露聚糖 在细菌群体中，以增强面对环境挑战的整体适应性。这将 为确定潜在的干预点提供基础， 细菌CPS生产和去殖民化特定的生态位。